title: HDACs link the DNA damage response, processing of double-strand breaks and autophagy.
abstract: Protein acetylation is mediated by histone acetyltransferases (HATs) and deacetylases (HDACs), which influence chromatin dynamics, protein turnover and the DNA damage response. ATM and ATR mediate DNA damage checkpoints by sensing double-strand breaks and single-strand-DNA-RFA nucleofilaments, respectively. However, it is unclear how acetylation modulates the DNA damage response. Here we show that HDAC inhibition/ablation specifically counteracts yeast Mec1 (orthologue of human ATR) activation, double-strand-break processing and single-strand-DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CtIP) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3, and one HAT, Gcn5, have key roles in these processes. We also find that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of hda1 and rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor, also causes Sae2 degradation. We propose that Rpd3, Hda1 and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand-break processing with autophagy.
authors.affiliation: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy.
authors.forename: Thomas
authors.initials: T
authors.lastname: Robert
authors.affiliation: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Vanoli
authors.affiliation: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy.|LBNL, Department of Genome Biology, Berkeley, California 94710-2722, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Chiolo
authors.affiliation: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy.
authors.forename: Ghadeer
authors.initials: G
authors.lastname: Shubassi
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032-2704, USA.
authors.forename: Kara A
authors.initials: KA
authors.lastname: Bernstein
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, New York 10032-2704, USA.
authors.forename: Rodney
authors.initials: R
authors.lastname: Rothstein
authors.affiliation: European Institute of Oncology, IFOM-IEO campus, Milan 20139, Italy.
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.affiliation: Cogentech, Milan 20139, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Parazzoli
authors.affiliation: Cogentech, Milan 20139, Italy.
authors.forename: Amanda
authors.initials: A
authors.lastname: Oldani
authors.affiliation: European Institute of Oncology, IFOM-IEO campus, Milan 20139, Italy.|DSBB-Università degli Studi di Milano, Milan 20139, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy.|DSBB-Università degli Studi di Milano, Milan 20139, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Foiani
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000626:Aminopeptidases / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071190:Autophagy-Related Protein 8 Family; D000071183:Autophagy-Related Proteins; D043171:Chromosomal Instability; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004720:Endonucleases / Q000737:chemistry / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology; D000099224:p300-CBP-Associated Factor
chemical_list: D000626:Aminopeptidases; D000071190:Autophagy-Related Protein 8 Family; D000071183:Autophagy-Related Proteins; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D014635:Valproic Acid; C113757:ATG8 protein, S cerevisiae; C107849:SAE2 protein, S cerevisiae; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor; C477823:ATG1 protein, S cerevisiae; C088937:MEC1 protein, S cerevisiae; C500749:target of rapamycin protein, S cerevisiae; C094191:MRE11 protein, S cerevisiae; C028450:exodeoxyribonuclease I; C019689:APE1 protein, S cerevisiae; C499673:HDA1 protein, S cerevisiae; C071665:RPD3 protein, S cerevisiae